First we studied, whether Mg2+ ions can potentiate the effect of DigiFab on the restoration of erythrocyte NKA activity ex vivo in PE vs. control pregnancy. We have examined the effect of DigiFab, Mg2+ and a combination of both on erythrocyte NKA activity in patients with PE. In erythrocytes from patients with uncomplicated pregnancies, we compared ex vivo inhibitory activity of incremental MBG concentration in the absence or presence of Mg2+, or combination of Mg2+ and DigiFab. Three-fold elevated plasma MBG in PE patients was associated with a 2.5-fold decrease of erythrocyte NKA activity vs. control. Preincubation of erythrocytes with Mg2+ or DigiFab increased NKA activity, and combination of both Mg2+ and DigiFab restored NKA activity to control level. NKA-inhibitory activity of MBG in control erythrocytes is shifted to the right by Mg2+. Combination of Mg2+ and DigiFab significantly potentiated immunoneutralizing effect of DigiFab on MBG, making NKA less sensitive to MBG. These findings indicate that magnesium is capable of increasing the efficacy of DigiFab in immunoneutralization of MBG-induced NKA inhibition in PE with a high probability to potentiate anti-hypertensive effect of DigiFab, which may have an important clinical application as antihypertensive therapy in PE. In a second study, we first measured plasma MBG levels and performed comprehensive clinical, laboratory, and echocardiographic assessment in 245 patients with heart failure (HF). All-cause mortality, cardiac transplantation, and HF hospitalization were tracked for 5 years. In our study cohort, median interquartile range MBG was 0.58 (0.38-0.81) nM. Higher MBG was associated with higher myeloperoxidase (MPO, r=0.42, p<0.0001), BNP (r=0.25, p=0.001), and asymmetric dimethylarginine (ADMA, r=0.32, p<0.001). Elevated levels of MBG were associated with measures of worse right ventricular function (RV s: r= -0.39, p<0.0001) and predicted increased risk of adverse clinical outcomes (MBG > 574 pM: HR 1.58 (1.10-2.31), p=0.014) even after adjustment for age, gender, diabetes mellitus, and ischemic etiology. In an animal validation study, a left anterior descending coronary artery ligation model of heart failure led to increases in MBG, while infusion of MBG into mice for 4 weeks led to significant increases in MPO, ADMA, and cardiac fibrosis. In the setting of heart failure, elevated plasma levels of MBG are associated with right ventricular dysfunction and predict worse long-term clinical outcomes in multivariable models adjusting for established clinical and biochemical risk factors. Infusion of MBG appears to directly contribute to increased nitrative stress and cardiac fibrosis. In our third preliminary clinical study in the junior CRF patients (n=21; 9 females and 12 males), levels of MBG progressively increased with an advancing CRF stage, reaching the highest levels at the hemodialysis stage (2.15 +/- 0.26 nM vs. 0.18 +/- 0.01 nM) compared to the healthy control. In adult CRF patients (n=12; 56+/-4 years), the level of MBG increased 3-fold vs. healthy control (n=9, age 52 +/- 5 years). Hemodialysis in adult CRF patients reduced plasma MBG concentration, but not to the control levels. Summary: These findings indicate that MBG in PE and CRF patients may be an important target for a therapeutic application of 3E9 anti-MBG mAb, which are currently in the process of humanization.